Histidine-rich glycoprotein (HRGP) is a multifunctional plasma protein of unclear physiologic significance. It not only binds proteins (plasminogen, fibrinogen, thrombospondin, vitronectin, immunoglobulin G, complement components), but also heparin, transition metals, and heme, and binds to several types of cells (T-lymphocytes, macrophages, platelets). Therefore, it may be a modulator of fibrinolysis, an immunoregulator, and a carrier of trace metals. The interaction of HRGP with platelets and ultimately how this might impact on platelet- dependent processes in fibrinolysis are areas of interest. A method for purifying HRGP from fresh plasma was previously developed, and more recently the protein has been used in a variety of studies. Discovered so far are several types of interaction between HRGP and platelets: (1) HRGP binds saturably to platelets when it is liganded to a transition metal (e.g., zinc); (2) plasminogen also promotes HRGP binding to platelets, although HRGP reduces the affinity of plasminogen binding to platelets; (3) zinc-liganded HRGP augments plasminogen binding to platelets; (4) in the presence of HRPG (with or without zinc) platelet- dependent activation of plasminogen by tissue plasminogen activator is increased. These observations suggest a complex role for HRPG in regulating fibrinolysis in a platelet-rich fibrin clot.